Drug products: Ezetimib Actavis, Ezetimib Aristo, Ezetimib Krka, Ezetimib Medical Valley, Ezetimib Sandoz, Ezetimib STADA, Ezetimib/Simvastatin 2care4, Ezetimib/Simvastatin Ebb, Ezetimib/Simvastatin Glenmark, Ezetimib/Simvastatin Krka, Ezetimibe Accord, Ezetimibe Mylan, Ezetimibe Orion, Ezetrol, Ezetrol®, Inegy, Inegy®
ATC code: C10AX09, C10BA02
Randomized placebo-controlled studies show conflicting results whether the combination ezetimibe + statin reduce lipid levels to a larger extent in hypercholesterolemic men than women. When used as monotherapy, ezetimibe have been shown to reduce lipid levels to similar extent in men and women.
In our opinion, the described differences do not motivate differentiated dosing or treatment in men and women.
Healthy men and women receiving ezetimibe 20 mg for 10 days showed similar pharmacokinetics . However, a study in healthy Chinese patients (6 men, 6 women) receiving a single oral dose of ezetimibe/-simvastatin 10/40 mg showed that ezetimibe AUC was higher in women, and the difference remained even after correction for body weight .
The original manufacturer report that ezetimibe 10 mg once daily for 10 days resulted in higher (<20%) plasma concentrations in women than in men . In another study by the manufacturer, women had 13-22% higher mean Cmax and AUC of ezetimibe than men after receiving 20 mg once daily for 10 days. They concluded that the difference partly may be due to difference in body weight . The difference has not been adjudicated to be large enough to warrant dosage adjustment based on sex .
There is a lack of studies reporting outcome data (mortality and morbidity) with an analysis of sex differences of treatment with ezetimibe .
Combination therapy with statins
A meta-analysis consisting of 27 double-blind, active- or placebo-controlled efficacy trials in hypercholesterolemic patients, assessed sex-related efficacy in patients treated with statin + ezetimibe (5389 men, 5142 women) or statin monotherapy (6140 men, 5607 women). Patients treated with the combination had almost twice the percentage reduction in lipid levels than patients treated with statin only, and men had slightly greater reductions than women. However, as the sex difference was very small (<2%), it’s probably of no clinical significance . The finding that men had greater lipid levels reductions than women has also been seen in patients with type 2 diabetes (59 men, 76 women) .
Contrary to the findings in the above mentioned large meta-analysis, other studies (not included in this meta-analysis) have not reported sex differences in reduction of lipid levels [9-12]. A meta-analysis consisting of three Phase III trials comparing simvastatin-ezetimibe (591 men, 645 women) and simvastatin monotherapy (589 men, 645 women) found some reductions in lipid levels among patients treated with the combination than simvastatin only (around -52% vs. -48%), and results were similar in men and women . Ezetimibe-simvastatin has also been found to reduce hs-CRP levels more than simvastatin monotherapy (-33% vs -14%), with similar reductions in men and women .No sex differences in the odds of achieving LDL-C targets were shown in a randomized, double-blind, placebo-controlled study comparing simvastatin-ezetimibe (30 men, 26 women) and simvastatin monotherapy (32 men, 24 women) .A post-hoc analysis of two randomized, double-blind trials comparing atorvastatin-ezetimibe and atorvastatin monotherapy showed somewhat more pronounced reductions in lipid levels in patients treated with the combination compared with atorvastatin only (around-29% vs. -11%), and results were similar in men and women .
The efficacy of ezetimibe 10 mg/day in patients with primary (non-familiar) hypercholesterolemia (434 men, 458 women) was analyzed in a randomized, double-blind, placebo-controlled study and showed LDL levels to be similarly reduced in men and women .Ezetimibe as monotherapy (10 men, 14 women) or in combination with a statin or fenofibrate (10 men, 16 women) were compared in hypercholesterolic Japanese patients. In multivariate analysis, both treatments reduced lipid levels in a similar way in both sexes .In children 6-10 years old with hypercholesterolemia, ezetimibe monotherapy reduced LDL-C levels to a similar extent in girls and boys, as shown in a randomized, double-blind, placebo-controlled study (59 boys, 79 girls). .
In a meta-analysis comparing statin + ezetimibe and statin monotherapy (see Effects), women reported more adverse events, such as gastrointestinal-related and allergic reactions for all included treatments. No significant sex differences in myopathy were reported .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Treatment with simvastatin-ezetimibe has been associated with cancer . A follow-up of patients participating in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (820 men, 539 women) investigated the incidence of cancer and total mortality during 21 months after the end of trial. However, this study showed no association between simvastatin-ezetimibe treatment and an increased risk of new cancers or mortality, and there were no differences in hazard ratios between men and women .
Date of litterature search: 2016-10-17
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson